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Immune checkpoint Inhibitor–Induced diarrhea and Colitis: Incidence and Management. A systematic review and Meta-analysis

Open AccessPublished:July 26, 2022DOI:https://doi.org/10.1016/j.ctrv.2022.102440

      Highlights

      • The incidence of anti-PD-1/PD-L1-induced diarrhea and colitis is low.
      • A high incidence of colitis was observed after ipilimumab combined with nivolumab.
      • Diarrhea but not colitis was frequently observed after anti-PD-[L]1 and chemotherapy/TKI.
      • Differentiation between chemotherapy/TKI and ICI-induced diarrhea is challenging.
      • Tailoring and optimization of the management of low-grade diarrhea are suggested.

      Abstract

      Background

      Immune checkpoint inhibitors (ICIs) have improved cancer outcomes. However, immune-related adverse effects are common. The aim was to investigate the incidence of diarrhea and colitis of ICIs alone and in combination with chemotherapy or tyrosine kinase inhibitors (TKIs), histopathological findings, and management.

      Methods

      Two separate studies, including meta-analyses, were performed. Key inclusion criteria were for Study I) phase I-IV trials, and data on diarrhea and/or colitis; for Study II) studies describing histopathologic and endoscopic findings and/or biologic treatment for ICI-induced colitis.

      Results

      The incidence of anti-PD-1/PD-L1 antibody-induced diarrhea and colitis was 10% and 2%, respectively, with no clinically relevant differences between the compounds. The CTLA-4 inhibitor, ipilimumab, induced diarrhea and colitis in 33% and 7% of patients, respectively, whereas the incidence of diarrhea and colitis following ipilimumab combined with nivolumab was 21%-37% and 4%-8%, depending on regimen. The incidence of all-grade diarrhea following ICIs combined with chemotherapy or TKIs was high (17%-56%), whereas only 0.5% of patients developed severe (≥grade 3) colitis. The main patterns of histopathologic presentation after PD-1/CTLA-4 inhibitor mono- or combination therapy were acute and chronic active colitis and microscopic colitis-like. Infliximab and vedolizumab were equally effective against ICI-induced colitis.

      Conclusion

      Expanding treatment options include combinations of ICIs and chemotherapy/TKI with a high incidence of diarrhea and a low incidence of colitis; thus, a potential risk of overtreatment with corticosteroids exists. We suggest a more tailored approach, particularly for the management of low-grade diarrhea. Prospective clinical trials are needed to refine management.

      Keywords

      Introduction

      The introduction of immune checkpoint inhibitors (ICIs) for different types of cancer constitutes a major breakthrough in the improvement of disease outcomes [
      • Ribas A.
      • Wolchok J.D.
      Cancer immunotherapy using checkpoint blockade.
      ]. However, ICIs can cause various immune-related adverse events (irAEs) [
      • Postow M.A.
      • Sidlow R.
      • Hellmann M.D.
      Immune-related adverse events associated with immune checkpoint blockade.
      ]. Following the initiation of ICIs, lower gastrointestinal (GI) events ranging from mild diarrhea to severe colitis [
      • Martins F.
      • Sofiya L.
      • Sykiotis G.P.
      • et al.
      Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.
      ] are commonly reported after 6–8 weeks, although they may occur later or after treatment discontinuation [
      • Geukes Foppen M.H.
      • Rozeman E.A.
      • van Wilpe S.
      • et al.
      Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
      ,
      • Marin-Acevedo J.A.
      • Chirila R.M.
      • Dronca R.S.
      Immune checkpoint inhibitor toxicities.
      ,
      • Som A.
      • Mandaliya R.
      • Alsaadi D.
      • et al.
      Immune checkpoint inhibitor-induced colitis: a comprehensive review.
      ,
      • Wang Y.
      • Abu-Sbeih H.
      • Mao E.
      • et al.
      Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson.
      ,
      • Yamauchi R.
      • Araki T.
      • Mitsuyama K.
      • et al.
      The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review.
      ].
      As most patients show primary or adaptive resistance to monotherapy, the use of combinations of ICIs [
      • Wei Y.
      • Du Q.
      • Jiang X.
      • et al.
      Efficacy and safety of combination immunotherapy for malignant solid tumors: a systematic review and meta-analysis.
      ] and other drugs (e.g., chemotherapy and tyrosine kinase inhibitors [TKIs]) is rapidly expanding, albeit at the cost of increased toxicity. Present guidelines, based on results from retrospective studies of ICI-induced diarrhea/colitis, recommend a universal approach for management [
      • Fan C.
      • Naidoo J.
      Multidisciplinary approach to immune-mediated diarrhea and colitis from immunotherapy for cancer.
      ]. Accordingly, a risk estimation of intestinal complications across various ICIs and combination regimens is essential to optimize treatment.
      This systematic review and meta-analysis focused on the incidence of ICI-induced diarrhea and colitis with monotherapy, combination therapy, as well as pathology, and management hereof.

      Methods

      Registration

      The study protocol was registered in the international prospective register of systematic reviews PROSPERO on May 20, 2020 (ID CRD42020187473).

      Data sources and searches

      This systematic review was performed following the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA guidelines [
      • Higgins J.T.J.
      • Chandler J.
      • Cumpston M.
      • Li T.
      Cochrane Handbook for systematic reviews of interventions version 6.2 (updated February 2021).
      ,
      • Hutton B.
      • Salanti G.
      • Caldwell D.M.
      • et al.
      The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.
      ,
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ,
      • Zorzela L.
      • Loke Y.K.
      • Ioannidis J.P.
      • et al.
      PRISMA harms checklist: improving harms reporting in systematic reviews.
      ] (Suppl. Table 1). We performed two separate literature searches on Medline, Embase, and Central (Studies I, IIa and IIb (studies for IIa and b were performed in one search strategy)). In our search, no restrictions on language or publication date were applied. Search strategies are shown in the Supplement.
      Screening was performed independently by two authors (DLN and OHN). Full-text articles were obtained from the relevant records and reviewed for eligibility. Disagreements regarding eligibility were discussed with the coauthors until a consensus was reached.

      Study selection

      Inclusion criteria for Study I were adult patients with malignancies treated with ICIs approved by the U.S. Food and Drug Administration (FDA) or European Medicine Agency (EMA), phase I-IV trials, and data on diarrhea and/or colitis. When several publications existed on the same study, we extracted all available data from the different publications. Studies without new safety data were excluded. Case reports, retrospective analyses, letters, reviews, and editorials were also excluded. Furthermore, escalation studies, studies with < 10 patients in each group or several doses reported together, and studies on intratumoral injection were excluded. For Study IIa, all studies describing histopathologic and endoscopic findings in the GI tract among patients with ICI-induced colitis were included. For Study IIb, phase I-IV or retrospective studies (≥5 patients) of biologic treatment (e.g., tumor necrosis factor [TNF] monoclonal antibodies [
      • Nielsen O.H.
      • Ainsworth M.A.
      Tumor necrosis factor inhibitors for inflammatory bowel disease.
      ]/monoclonal antibodies to the bowel-specific α4β7-integrin [
      • Battat R.
      • Dulai P.S.
      • Jairath V.
      • et al.
      A product review of vedolizumab in inflammatory bowel disease.
      ]) in patients with ICI-induced colitis were included. Furthermore, for Study IIb, conference abstracts were included if no full-length articles were available. Reference lists from the articles were screened for relevant studies. Only studies published in English were included.

      Data extraction

      The following data were extracted independently: Study I (DLN and IMC): first author, publication year, interventions, tumor type, phase, National Clinical Trial (NCT) number, number of patients, duration of treatment, follow-up, diarrhea/colitis (treatment-related adverse event [TRAE] grade 1–4 and grade 3–4), death due to diarrhea/colitis, discontinuation due to toxicity, specifications concerning adverse event reporting, and treatment of side effects. Study IIa (OHN and LK): first author, publication year, number of patients, histology grading system applied, and conclusions dealing with pathology depicted. For Study IIb (OHN and DLN): first author, publication year, intervention, phase, NCT number, number of patients, tumor type and ICI, patient characteristics (prednisolone exposure, prior biologic therapy), diagnostic criteria, number of doses, and efficacy (remission rate).

      Assessment of risk of bias

      The risk of bias was assessed in Study I independently by DLN and IMC using the McMaster Quality Assessment Scale for Harms [

      Chou R, Aronson N, Atkins D et al. Assessing Harms When Comparing Medical Interventions. Methods Guide for Effectiveness and Comparative Effectiveness Reviews, Rockville (MD)2008.

      ]. No quality assessment was performed for Study IIa. The Newcastle-Ottawa Quality Assessment was conducted independently by DLN and OHN for Study IIb [

      Wells GA SB, O'Connell D, Petersen J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2021. www.ohri.ca.

      ]. Controversies were resolved via discussion with the coauthors.

      Pharmacovigilance databases

      Data concerning colitis, enterocolitis and intestinal perforation registered by May 30, 2021 were collected from in VigiLyze (integrated with the global adverse drug reaction database VigiBase), EudraVigilance (system for managing and analyzing information on suspected adverse reactions to medicines that have been authorized or are being studied in clinical trials in the European Economic Area, operated by the EMA), and FAERS (FDA Adverse Event Reporting System) databases.

      Statistical analysis

      Incidences of diarrhea/colitis were calculated with 95% Confidence Intervals (CI)s using the metaprop command in STATA 17.1 (StataCorp, College Station, TX) and by applying the Freeman–Tukey double-arcsine transformation to control for studies with no events. To explore the difference between ICIs in the incidence of diarrhea/colitis, a random-effects meta-analysis was performed, assuming heterogeneity due to differences in participants and diseases. Heterogeneity was evaluated by assessing the I2 statistics as the percentage of variance attributable to inconsistencies. Differences between the incidences of different ICIs were assessed using Cochran’s Q test. Because of multiple testing, a significance level of 0.001 was applied when comparing the incidence of GI toxicity for individual ICIs.

      Results

      Incidences of diarrhea and colitis

      Eight ICIs are currently approved for clinical use by the FDA and EMA (Suppl. Table 2). Our search, updated April 21, 2021, identified 6,860 records. In total, 434 full-text articles met our inclusion criteria, representing 411 unique studies, and 316 studies were included in the meta-analysis (some studies were included in several analyses; Suppl. Fig. 1). The studies are listed in Suppl. Table 3 (A-G). In general, ICIs targeting PD-1/PD-L1 have been combined with every conceivable drug category. Toxicity was manageable; however, there are a few exceptions. Three studies were terminated because of liver toxicity [
      • Spigel D.R.
      • Reynolds C.
      • Waterhouse D.
      • et al.
      Phase 1/2 study of the safety and tolerability of nivolumab plus crizotinib for the first-Line treatment of anaplastic lymphoma kinase translocation - positive advanced non-small cell lung cancer (CheckMate 370).
      ,
      • Yamazaki N.
      • Uhara H.
      • Fukushima S.
      • et al.
      Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma.
      ,
      • Yang J.C.
      • Gadgeel S.M.
      • Sequist L.V.
      • et al.
      Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation.
      ], and one study was discontinued because of interstitial lung disease [
      • Yang J.C.
      • Shepherd F.A.
      • Kim D.W.
      • et al.
      Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report.
      ].
      In total, 397 studies used the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4 or 5, for grading toxicity [

      National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE). November 27, 2017. 2017.

      ]. In ten studies, findings were unclear or the version was not specified; only four studies did not use NCI-CTCAE for reporting adverse events (AE). Nonetheless, the grading of diarrhea and colitis was similar between the two CTCAE versions (Suppl. Table 4). The risk of bias and methodological quality is displayed and summarized in Suppl. Tables 5 (A-G) and 6. In general, the quality of the included studies was high.

      Incidence of Diarrhea/Colitis associated with PD-1 inhibition

      The incidences of diarrhea and colitis are shown in Fig. 1 and Suppl. Table 7. The incidence of grade 1–4 and grade 3–4 diarrhea after a 200 mg dosage of pembrolizumab every three weeks (Q3W; the standard dose) was 9.5% and 0.3%, respectively, whereas the incidence of grade 1–4 and grade 3–4 colitis was 1.3% and 0.4%, respectively.
      Figure thumbnail gr1
      Fig. 1Forest plots of the incidences of grade 1–4 diarrhea (A) and colitis (B) and grade 3–4 diarrhea (C) and colitis (D) following immune checkpoint inhibitor therapy.
      Studies investigating the standard flat dose of nivolumab (240 mg; Q2W) reported incidence of grade 1–4 and grade 3–4 diarrhea of 11.6% and 0.04%, respectively. The incidence of grade 1–4 and grade 3–4 colitis was 0.2% and 0.0%, respectively. The current recommended dose of 480 mg Q4W was part of the intervention of eight studies [
      • Azad N.S.
      • Gray R.J.
      • Overman M.J.
      • et al.
      Nivolumab is effective in mismatch repair-deficient noncolorectal cancers: results from arm Z1D-A subprotocol of the NCI-MATCH (EAY131) study.
      ,
      • Kelly R.J.
      • Ajani J.A.
      • Kuzdzal J.
      • et al.
      Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer.
      ,
      • Kim R.D.
      • Chung V.
      • Alese O.B.
      • et al.
      A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer.
      ,
      • Lebbe C.
      • Meyer N.
      • Mortier L.
      • et al.
      Evaluation of two dosing regimens for vivolumab in combination with ipilimumab in patients with advanced melanoma: Results from the phase IIIb/IV CheckMate 511 Trial.
      ,
      • McKay R.R.
      • McGregor B.A.
      • Xie W.
      • et al.
      Optimized management of nivolumab and ipilimumab in advanced renal cell carcinoma: a response-based phase II study (OMNIVORE).
      ,
      • Pelster M.S.
      • Gruschkus S.K.
      • Bassett R.
      • et al.
      Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study.
      ,
      • Perez B.A.
      • Kim S.
      • Wang M.
      • et al.
      Prospective single-arm phase 1 and 2 study: ipilimumab and nivolumab with thoracic radiation therapy after platinum chemotherapy in extensive-stage small cell lung cancer.
      ,
      • Peters S.
      • Felip E.
      • Dafni U.
      • et al.
      Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial.
      ] (Suppl. Table 3); however, data for this regimen could not be extracted as these studies included various doses of nivolumab and reported the combined toxicity.
      Cemiplimab was investigated in three studies, including two dose regimens (3 mg/kg Q2W or 350 mg Q3W). The overall incidence of grade 1–4 and grade 3–4 diarrhea was 11.5% and 0.04%, respectively, and the incidence of grade 1–4 and grade 3–4 colitis was 0.8% and 0.04%, respectively.
      The overall incidence of grade 1–4 and grade 3–4 diarrhea following treatment with a PD-1 inhibitor was 10.7% and 0.2%, respectively, and the incidence of grade 1–4 and grade 3–4 colitis was 1.2% and 0.2%, respectively (Fig. 2 and Suppl. Table 8). Four deaths due to colitis were recorded in the 19,715 patients (one study did not report cause of death (1008 patients [
      • Nathan P.
      • Ascierto P.A.
      • Haanen J.
      • et al.
      Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172).
      ])). The discontinuation rate due to occurrence of diarrhea and/or colitis was 6.1%.
      Figure thumbnail gr2
      Fig. 2Forest plot of incidences of any grade diarrhea and colitis and grade 3–4 diarrhea and colitis following PD-1 and PD-L1 inhibitor therapy.

      Incidence of Diarrhea/Colitis associated with PD-L1 inhibition

      The incidences of diarrhea and colitis are shown in Fig. 1 and Suppl. Table 7. The incidence of grade 1–4 and grade 3–4 diarrhea following a 1,200 mg dosage of atezolizumab Q3W was 8.8% and 0.1%, respectively, whereas the incidence of grade 1–4 and grade 3–4 colitis was 0.6% and 0.3%, respectively.
      The incidence of grade 1–4 and grade 3–4 diarrhea after the currently recommended flat dose of 1,500 mg of durvalumab Q4W was 6.1% and 0.0%, respectively. Grade 1–4 and grade 3–4 colitis were reported with an incidence of 0.2% and 0.06%, respectively.
      For avelumab, the incidence of grade 1–4 and grade 3–4 diarrhea was 6.7% and 0.0%, respectively, whereas the incidence of grade 1–4 and grade 3–4 colitis was 0.2% and 0.0%, respectively.
      The overall incidence of grade 1–4 and grade 3–4 diarrhea after treatment with a PD-L1 inhibitor was 8.0% and 0.02%, respectively, and the overall incidence of grade 1–4 and grade 3–4 colitis was 0.3% and 0.04%, respectively (Fig. 2 and Suppl. Table 8). Among 10,035 treated patients, two deaths due to colitis were recorded (one study did not report cause of death (237 patients [
      • Ferris R.L.
      • Haddad R.
      • Even C.
      • et al.
      Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.
      ])). The discontinuation rate due to diarrhea and/or colitis was 5.4%.

      Incidence of Diarrhea/Colitis associated with PD-1/PD-L1 monotherapy

      A comparison of the incidence of diarrhea/colitis after PD-1 and PD-L1 inhibition showed that the incidence of diarrhea grade 1–4 (10.6% v 8.0%, P < 0.002), diarrhea grade 3–4 (0.2% v 0.02%, P < 0.002), and colitis grade 1–4 (1.2% v 0.3%, P < 0.001) were significantly higher for PD-1 inhibitors. However, the incidence of colitis grade 3–4 (0.2% v 0.04%, P = 0.143) did not differ between the compounds. Furthermore, findings for the individual compounds were inconsistent, and the differences did not seem to be clinically relevant (Suppl. Table 9).

      Incidence of Diarrhea/Colitis associated with CTLA-4 inhibition

      The incidence of diarrhea/colitis following ipilimumab treatment differed significantly between the doses (Fig. 1 and Suppl. Table 7). Grade 1–4 and grade 3–4 diarrhea after a 3 mg/kg dosage of ipilimumab was 28.6% and 5.9%, respectively, with the incidence of grade 1–4 and grade 3–4 colitis at 11.2% and 4.9%, respectively. Nine deaths due to fulminant colitis/intestinal perforation were recorded in 2,387 patients (cause of death reported in all studies). Thus, the incidence of diarrhea/colitis associated with a CTLA-4 inhibitor was significantly higher than that associated with PD-1/PD-L1 monotherapy (P < 0.001 for all analyses).

      Incidence of Diarrhea/Colitis associated with PD-1/PD-L1 inhibition in combination with ipilimumab

      The incidence of grade 1–4 and grade 3–4 diarrhea after a 3 mg/kg dosage of nivolumab and a 1 mg/kg dosage of ipilimumab Q3W, the currently recommended doses [

      OPDIVO. INN-nivolumab-European Medicines Agency. 2021.

      ] for renal cell carcinoma and colorectal cancer, was 21.0% and 2.7%, respectively, whereas the incidence of grade 1–4 and grade 3–4 colitis was 3.6% and 1.2%, respectively. For a 1 mg/kg dosage of nivolumab and a 3 mg/kg dosage of ipilimumab Q3W, the currently recommended doses for melanoma [

      OPDIVO. INN-nivolumab-European Medicines Agency. 2021.

      ] and hepatocellular carcinoma [
      • Yau T.
      • Kang Y.K.
      • Kim T.Y.
      • et al.
      Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial.
      ], the incidence of grade 1–4 and grade 3–4 diarrhea was 36.6% and 7.4%, respectively, whereas the incidences of grade 1–4 and grade 3–4 colitis were 8.2% and 5.6%, respectively. Compared with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, the incidence of severe colitis was significantly higher for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (P = 0.001; Fig. 3 and Suppl. Table 10). Finally, nivolumab 3 mg/kg Q3W and ipilimumab 1 mg/kg Q6W has been approved by FDA for treatment of non-small cell lung cancer [
      • Paz-Ares L.G.
      • Ramalingam S.S.
      • Ciuleanu T.E.
      • et al.
      First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial.
      ]. The incidence of grade 1–4 and grade 3–4 diarrhea was 20.3% and 1.6%, respectively, whereas the incidences of grade 1–4 and grade 3–4 colitis were 4.7% and 2.7%, respectively.
      Figure thumbnail gr3
      Fig. 3Forest plot of incidences of any grade diarrhea and colitis and grade 3–4 diarrhea and colitis following PD-1 inhibitor and CTLA-4 inhibitor therapy (nivolumab and ipilimumab).
      For all combinations, the incidence of diarrhea and colitis was significantly higher than that of PD-1/PD-L1 inhibitors (P < 0.001), whereas the incidence of grade 5 events did not increase (cause of death reported in all studies).

      Incidence of Diarrhea/Colitis associated with PD-1/PD-L1 inhibition in combination with chemotherapy

      The incidence of all grade of diarrhea was approximately three times higher following treatment with a PD-1 inhibitor in combination with platin-based chemotherapy than for monotherapy (29.3%). Furthermore, the incidence of grade 3–4 diarrhea increased significantly (2.2%). The incidence of grade 1–4 and grade 3–4 diarrhea after platin-based chemotherapy alone in randomized trials ranged from 19% to 24% and 0% to 3%, respectively [
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ,
      • Paz-Ares L.
      • Luft A.
      • Vicente D.
      • et al.
      Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer.
      ,
      • Galsky M.D.
      • Mortazavi A.
      • Milowsky M.I.
      • et al.
      Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer.
      ]. The incidence of grade 1–4 and grade 3–4 colitis following a PD-1 inhibitor plus platin-based chemotherapy was 1.6% and 0.6%, respectively (Fig. 4 A, Suppl. Tables 11 and 12).
      Figure thumbnail gr4
      Fig. 4Forest plot of incidence of any grade diarrhea and colitis and grade 3–4 diarrhea and colitis following PD-1 and PD-L1 inhibitor therapy in combination with platin-based (A) and taxane-based chemotherapy (B).
      The incidence of diarrhea/colitis following a PD-L1 inhibitor in combination with platin-based chemotherapy was comparable to that of PD-1 inhibitors in combination with platin-based chemotherapy (Fig. 4 A, Suppl. Tables 11 and 12).
      Few studies investigated taxane-based treatment. Following combination therapy with PD-1/PD-L1 inhibitors (5 studies each) and taxane-based chemotherapy, the incidence of grade 1–4 diarrhea was higher than that for combinations with platin (37%-40%). However, the incidences of severe diarrhea (approximately 2%) and colitis grade 3–4 (<0.5%) were low (Fig. 4 B, Suppl. Tables 13 and 14).

      Incidence of Diarrhea/Colitis associated with PD-1/PD-L1 inhibition in combination with other drugs

      Totally, 12 studies, including 1478 patients, investigated the combination of a PD-1/PD-L1 inhibitor and a TKI targeting angiogenesis (regorafenib/sunitinib (3 studies); lenvatinib/axitinib (9 studies)) (Suppl. Table 16). A high incidence of grade 1–4 (37%-54%) and grade 3–4 diarrhea (up to 9%) [
      • Atkins M.B.
      • Plimack E.R.
      • Puzanov I.
      • et al.
      Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: long-term efficacy and safety from a phase Ib trial.
      ,
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ] was reported for these combinations. However, the incidence of colitis of grade 1–4 was low (approximately 2%). Diarrhea seemed to be much less frequent when PD-1/PD-L1 inhibitors were combined with bevacizumab (16%) (7 studies; 1152 patients) (Suppl. Table 16) [
      • Lin Z.
      • Yang Y.
      • Huang Y.
      • et al.
      Vascular endothelial growth factor receptor tyrosine kinase inhibitors versus bevacizumab in metastatic colorectal cancer: a systematic review and meta-analysis.
      ]. Only few studies evaluated the combination of an ICI and TKI aimed for other targets. The combination of a PD-1/PD-L1 inhibitor and a TKI targeting epidermal growth factor receptor (EGFR) has only been investigated in three small studies including 44 patients [
      • Yang J.C.
      • Gadgeel S.M.
      • Sequist L.V.
      • et al.
      Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation.
      ,
      • Yang J.C.
      • Shepherd F.A.
      • Kim D.W.
      • et al.
      Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report.
      ,
      • Gettinger S.
      • Hellmann M.D.
      • Chow L.Q.M.
      • et al.
      Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC.
      ]. The combination was followed by grade 1–4 diarrhea in 29% of patients with low incidence of severe diarrhea/colitis (3%). Finally, ICI in combination with the anaplastic lymphoma kinase (ALK) inhibitors, crizotinib or ceritinib, has been evaluated in one study including 49 patients [
      • Felip E.
      • de Braud F.G.
      • Maur M.
      • et al.
      Ceritinib plus nivolumab in patients with advanced ALK-rearranged non-small cell lung cancer: results of an open-label, multicenter, phase 1B study.
      ]. The incidence of grade 1–4 diarrhea was 52%, whereas only one event of grade 3–4 diarrhea was reported in the ceritinib arm (1%) (Suppl. Table 16). Independent of treatment modality, the incidence of diarrhea seemed to be additive with no clinically relevant increase in the incidence of colitis.

      An overview from pharmacovigilance databases

      We collected data concerning colitis and intestinal perforation in VigiLyze, EudraVigilance, and FAERS databases registered by May 30, 2021 (Suppl. Table 17). Microscopic colitis was registered for all drugs except avelumab, which was probably due to a limited number of cases [
      • Awada G.
      • Ben Salama L.
      • De Cremer J.
      • et al.
      Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx).
      ]. Microscopic colitis accounted for 1%-3% of all reported colitis cases following PD-1/PD-L1 inhibitors, whereas the condition during treatment with ipilimumab accounted for 0.4%-0.7%. Fatal events and intestinal perforation were reported for all ICIs, however, most frequently reported with ipilimumab (Suppl. Table 17).

      Histopathology

      For Study IIa, 23 studies reporting on a total of 902 cases of biopsy-proven histopathologic changes in colitis induced by ICI therapy were identified (Suppl. Fig. 2 and Suppl. Table 18) [
      • Geukes Foppen M.H.
      • Rozeman E.A.
      • van Wilpe S.
      • et al.
      Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
      ,
      • Collins M.
      • Michot J.M.
      • Danlos F.X.
      • et al.
      Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Luo W.
      • et al.
      Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.
      ,
      • Adler B.L.
      • Pezhouh M.K.
      • Kim A.
      • et al.
      Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.
      ,
      • Bamias G.
      • Delladetsima I.
      • Perdiki M.
      • et al.
      Immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy.
      ,
      • Baroudjian B.
      • Lourenco N.
      • Pages C.
      • et al.
      Anti-PD1-induced collagenous colitis in a melanoma patient.
      ,
      • Beck K.E.
      • Blansfield J.A.
      • Tran K.Q.
      • et al.
      Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
      ,
      • Berman D.
      • Parker S.M.
      • Siegel J.
      • et al.
      Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma.
      ,
      • Chen J.H.
      • Pezhouh M.K.
      • Lauwers G.Y.
      • et al.
      Histopathologic features of colitis due to immunotherapy with anti-PD-1 antibodies.
      ,
      • Cheung V.T.F.
      • Gupta T.
      • Olsson-Brown A.
      • et al.
      Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?.
      ,
      • de Andrea C.E.
      • Perez-Gracia J.L.
      • Castanon E.
      • et al.
      Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors.
      ,
      • Gonzalez R.S.
      • Salaria S.N.
      • Bohannon C.D.
      • et al.
      PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.
      ,
      • Hayashi Y.
      • Hosoe N.
      • Takabayashi K.
      • et al.
      Clinical, endoscopic, and pathological characteristics of immune checkpoint inhibitor-induced gastroenterocolitis.
      ,
      • Herlihy J.D.
      • Beasley S.
      • Simmelink A.
      • et al.
      Flexible sigmoidoscopy rather than colonoscopy is adequate for the diagnosis of ipilimumab-associated colitis.
      ,
      • Marthey L.
      • Mateus C.
      • Mussini C.
      • et al.
      Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease.
      ,
      • Isidro R.A.
      • Ruan A.B.
      • Gannarapu S.
      • et al.
      Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.
      ,
      • Nahar K.J.
      • Rawson R.V.
      • Ahmed T.
      • et al.
      Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab.
      ,
      • Oble D.A.
      • Mino-Kenudson M.
      • Goldsmith J.
      • et al.
      Alpha-CTLA-4 mAb-associated panenteritis: a histologic and immunohistochemical analysis.
      ,
      • Pai R.K.
      • Pai R.K.
      • Brown I.
      • et al.
      The significance of histological activity measurements in immune checkpoint inhibitor colitis.
      ,
      • Verschuren E.C.
      • van den Eertwegh A.J.
      • Wonders J.
      • et al.
      Clinical, endoscopic, and histologic characteristics of ipilimumab-associated colitis.
      ,
      • Wang Y.
      • Abu-Sbeih H.
      • Mao E.
      • et al.
      Endoscopic and histologic features of immune checkpoint inhibitor-related colitis.
      ,
      • Yanai S.
      • Nakamura S.
      • Kawasaki K.
      • et al.
      Immune checkpoint inhibitor-induced diarrhea: clinicopathological study of 11 patients.
      ,
      • Zhang M.L.
      • Neyaz A.
      • Patil D.
      • et al.
      Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies.
      ]. Due to the large differences between study design and reporting methodology, a meta-analysis was not performed.

      Endoscopic features

      ICI-induced colitis may affect the entire colon or only segments and abnormal endoscopic findings can be either diffuse or patchy [
      • Gonzalez R.S.
      • Salaria S.N.
      • Bohannon C.D.
      • et al.
      PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.
      ]. In general, erosions and ulcerations at endoscopy are indicative of histopathologic findings of inflammation, although biopsies from a normal endoscopy may reveal both acute and chronic changes [
      • Cheung V.T.F.
      • Gupta T.
      • Olsson-Brown A.
      • et al.
      Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?.
      ]. Associated diffuse enteritis was present in one-quarter of patients and may occur even in the absence of any endoscopic findings of colitis [
      • Messmer M.
      • Upreti S.
      • Tarabishy Y.
      • et al.
      Ipilimumab-induced enteritis without colitis: a new challenge.
      ].

      Microscopic features

      The most common histopathological findings were increased mixed lymphoplasmacytic infiltrates in the lamina propria, and varying degrees of neutrophilic infiltration in the epithelium and crypts. Based on the large overlap between microscopic findings of other known types of colitis, ICI-induced colitis has been grouped into different histopathologic patterns [
      • Gonzalez R.S.
      • Salaria S.N.
      • Bohannon C.D.
      • et al.
      PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.
      ,
      • Isidro R.A.
      • Ruan A.B.
      • Gannarapu S.
      • et al.
      Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.
      ,
      • Patil P.A.
      • Zhang X.
      Pathologic manifestations of gastrointestinal and hepatobiliary injury in immune checkpoint inhibitor therapy.
      ] (Table 1), namely: (1) acute active colitis, (2) chronic active colitis, (3) microscopic colitis-like, (4) graft-versus-host disease-like, and (5) other types (i.e., mixed type, ischemic colitis-like, nonspecific inflammatory reactive changes).
      Table 1Histopathologic pattern and typical microscopic findings in patients with immune checkpoint inhibitor-induced colitis.
      Histopathologic patternTypical microscopic findings
      Acute active colitisCryptitis (intraepithelial neutrophils)

      Crypt abscesses (neutrophils in crypt lumen)

      Crypt atrophy and dropout

      Increased intraepithelial lymphocytes

      Increased epithelial apoptosis can be present

      Intraluminal apoptotic debris admixed with inflammatory cells in atrophic crypts can be present
      Chronic active colitis

      “IBD-like”
      Findings of active colitis

      Basal plasmacytosis

      Crypt architectural distortions

      Paneth cell metaplasia

      Mucin depletion

      Granulomas is relation to ruptured crypts
      Microscopic colitis including

      Lymphocytic colitis-like

      Collagenous colitis-like




      More than 20 intraepithelial lymphocytes per 100 epithelial cells

      A thickened subepithelial collagenous band > 10 µm
      GVHD-like/”apoptosis only”Increased number of crypt epithelial apoptosis without features of acute or chronic inflammation
      Ischemic colitis-likeWithered crypts

      Reactive epithelial changes

      Lamia propria fibrosis
      IBD, inflammatory bowel disease; GVHD, graft versus host disease.
      The most common pattern in the 902 cases was acute active colitis (44%), followed by chronic active colitis (32%), indicating that active inflammation with neutrophils was present in a minimum of 76% of cases (Suppl. Table 19). The inflammatory infiltrates were diffuse in the majority of cases and less often focal or patchy [
      • Bamias G.
      • Delladetsima I.
      • Perdiki M.
      • et al.
      Immunological characteristics of colitis associated with anti-CTLA-4 antibody therapy.
      ,
      • Chen J.H.
      • Pezhouh M.K.
      • Lauwers G.Y.
      • et al.
      Histopathologic features of colitis due to immunotherapy with anti-PD-1 antibodies.
      ,
      • Isidro R.A.
      • Ruan A.B.
      • Gannarapu S.
      • et al.
      Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.
      ]. Microscopic colitis with a predominance of the lymphocytic-like pattern was reported in 14% of cases. Only few studies have reported on the correlation between ICI type and specific histopathologic changes. Two studies found no correlation [
      • Geukes Foppen M.H.
      • Rozeman E.A.
      • van Wilpe S.
      • et al.
      Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
      ,
      • Pai R.K.
      • Pai R.K.
      • Brown I.
      • et al.
      The significance of histological activity measurements in immune checkpoint inhibitor colitis.
      ], but others reported that patients treated with anti-CTLA-4 were more likely to have acute active colitis and less likely to have chronic and microscopic colitis [
      • Isidro R.A.
      • Ruan A.B.
      • Gannarapu S.
      • et al.
      Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.
      ]. The fractions of cases with a specific histopathological pattern related to type of ICI treatment in all 902 cases are found in Suppl. Table 19, although not all studies specified whether the histopathologic changes were related to PD-1 and CTLA-4 as mono- or combination therapy. No data for PD-L1 as monotherapy, combinations with chemotherapy or TKIs were identified.
      None of the histopathological features reported for ICI-induced colitis were, however, specific. The acute colitis pattern showed similarities with acute intestinal infections and drug-induced colitis, whereas the active chronic colitis pattern shared features with inflammatory bowel disease (IBD) [
      • Chen J.H.
      • Pezhouh M.K.
      • Lauwers G.Y.
      • et al.
      Histopathologic features of colitis due to immunotherapy with anti-PD-1 antibodies.
      ,
      • Isidro R.A.
      • Ruan A.B.
      • Gannarapu S.
      • et al.
      Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.
      ]. Compared with ulcerative colitis, the number of apoptosis was higher in ICI-induced colitis [
      • Adler B.L.
      • Pezhouh M.K.
      • Kim A.
      • et al.
      Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.
      ]. The severity of inflammatory damage may predict clinical outcome [
      • Abu-Sbeih H.
      • Ali F.S.
      • Luo W.
      • et al.
      Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.
      ,
      • Nahar K.J.
      • Rawson R.V.
      • Ahmed T.
      • et al.
      Clinicopathological characteristics and management of colitis with anti-PD1 immunotherapy alone or in combination with ipilimumab.
      ]. Though, as with other types of colitis, the correlation between symptoms and endoscopic and histologic findings has been found to be only modest [
      • Geukes Foppen M.H.
      • Rozeman E.A.
      • van Wilpe S.
      • et al.
      Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
      ]. No consensus on the histopathologic grading of ICI-induced colitis exists; however, scoring indexes designed for inflammatory bowel disease can be used although they might not be fully feasible [
      • Marchal-Bressenot A.
      • Salleron J.
      • Boulagnon-Rombi C.
      • et al.
      Development and validation of the Nancy histological index for UC.
      ,
      • Mosli M.H.
      • Feagan B.G.
      • Zou G.
      • et al.
      Development and validation of a histological index for UC.
      ,
      • Ma C.
      • Pai R.K.
      • Schaeffer D.F.
      • et al.
      Recommendations for standardizing biopsy acquisition and histological assessment of immune checkpoint inhibitor-associated colitis.
      ]. Thus, both the Nancy Index and Robarts Histopathologic Index have been applied in retrospective analyses and were independently associated with the use of biologics and adverse ICI-induced colitis outcomes [
      • Cheung V.T.F.
      • Gupta T.
      • Olsson-Brown A.
      • et al.
      Immune checkpoint inhibitor-related colitis assessment and prognosis: can IBD scoring point the way?.
      ,
      • Pai R.K.
      • Pai R.K.
      • Brown I.
      • et al.
      The significance of histological activity measurements in immune checkpoint inhibitor colitis.
      ]. Nonetheless, these findings need to be validated in prospective studies.

      Therapy of ICI-Induced colitis

      For glucocorticoid-refractory cases with CTCAE grade 2 or higher diarrhea or colitis, guidelines recommend biologics at an early point with either infliximab (TNF inhibitor [
      • Nielsen O.H.
      • Ainsworth M.A.
      Tumor necrosis factor inhibitors for inflammatory bowel disease.
      ]) or vedolizumab (α4β7 anti-integrin [
      • Bergqvist V.
      • Hertervig E.
      • Gedeon P.
      • et al.
      Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.
      ]) [

      Haanen J, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl_4): iv119-iv142.

      ,
      • Thompson J.A.
      • Schneider B.J.
      • Brahmer J.
      • et al.
      NCCN guidelines insights: management of immunotherapy-related toxicities, Version 1.2020.
      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update.
      ]. To assess the efficacy of biologics, we identified 25 records (Suppl. Fig. 2): 20 publications with infliximab [
      • Geukes Foppen M.H.
      • Rozeman E.A.
      • van Wilpe S.
      • et al.
      Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Luo W.
      • et al.
      Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.
      ,
      • Herlihy J.D.
      • Beasley S.
      • Simmelink A.
      • et al.
      Flexible sigmoidoscopy rather than colonoscopy is adequate for the diagnosis of ipilimumab-associated colitis.
      ,
      • Marthey L.
      • Mateus C.
      • Mussini C.
      • et al.
      Cancer immunotherapy with anti-CTLA-4 monoclonal antibodies induces an inflammatory bowel disease.
      ,
      • Verschuren E.C.
      • van den Eertwegh A.J.
      • Wonders J.
      • et al.
      Clinical, endoscopic, and histologic characteristics of ipilimumab-associated colitis.
      ,
      • Zhang M.L.
      • Neyaz A.
      • Patil D.
      • et al.
      Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies.
      ,
      • Arriola E.
      • Wheater M.
      • Karydis I.
      • et al.
      Infliximab for ipilimumab-related colitis.
      ,
      • Franklin C.
      • Rooms I.
      • Fiedler M.
      • et al.
      Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.
      ,
      • Harding J.J.C.
      • Postow M.
      • Rocco K.
      • Dangelo S.
      • Dickson M.
      • Carvajal R.
      • et al.
      Infliximab for ipilimumab induced colitis in melanoma patients.
      ,
      • Hillock N.T.
      • Heard S.
      • Kichenadasse G.
      • et al.
      Infliximab for ipilimumab-induced colitis: a series of 13 patients.
      ,
      • Horvat T.Z.
      • Adel N.G.
      • Dang T.O.
      • et al.
      Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at emorial Sloan Kettering Cancer Center.
      ,
      • Hughes M.S.
      • Molina G.E.
      • Chen S.T.
      • et al.
      Budesonide treatment for microscopic colitis from immune checkpoint inhibitors.
      ,
      • Jain A.
      • Lipson E.J.
      • Sharfman W.H.
      • et al.
      Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.
      ,
      • Kadokawa Y.
      • Takagi M.
      • Yoshida T.
      • et al.
      Efficacy and safety of infliximab for steroid-resistant immune-related adverse events: a retrospective study.
      ,
      • Kim J.S.
      • Schattner M.A.
      • Gerdes H.
      • Markowitz A.J.
      • Kurtz R.C.
      • Ludwig E.
      • et al.
      Anti-PD-1 induced colitis: a case series of 25 patients.
      ,
      • Lesage C.
      • Longvert C.
      • Prey S.
      • et al.
      Incidence and clinical impact of anti-TNFalpha treatment of severe immune checkpoint inhibitor-induced colitis in advanced melanoma: The Mecolit Survey.
      ,
      • Mir R.S.
      • Shaw H.M.
      • Kuhan H.
      • Bataille V.
      • Vergis R.
      • Corner C.
      • et al.
      Cumulative corticosteroid exposure in patients experiencing checkpoint inhibitor toxicity.
      ,
      • Salgado A.C.C.
      • Giobbie-Hurder A.
      • Soria A.
      • Lawrence D.P.
      • Cortes J.
      • Sullivan R.J.
      Management of immune-mediated diarrhea and the impact of infliximab on outcome.
      ,
      • Sidhu M.S.
      • Kefford R.
      • Carlino M.
      Infliximab for the treatment of ipilimumab (anti CTLA4) and nivolumab/pembrolizumab (anti PD-1) associated colitis.
      ,
      • Spain L.C.
      • Au L.
      • Daniels E.
      • Chauhan D.
      • Ibraheim H.
      • Powell N.
      • Gore M.
      • Larkin J.
      • Turajlic S.
      • Yousaf N.
      Infliximab use in immunerelated diarrhea colitis.
      ], three with vedolizumab [
      • Bergqvist V.
      • Hertervig E.
      • Gedeon P.
      • et al.
      Vedolizumab treatment for immune checkpoint inhibitor-induced enterocolitis.
      ,
      • Zou F.S.
      • Shah A.Y.
      • Glitza I.C.
      • Richards D.
      • Thomas A.S.
      • Wany Y.
      Comparative study of vedolizumab and infliximab treatment in patients with immune-mediated diarrhea and colitis.
      ,
      • Harris J.F.
      • Faleck D.
      Effectiveness of vedolizumab in patients with refractory immunotherapy-related colitis: a case series.
      ], and two with both [
      • Zou F.S.
      • Shah A.Y.
      • Glitza I.C.
      • Richards D.
      • Thomas A.S.
      • Wany Y.
      Comparative study of vedolizumab and infliximab treatment in patients with immune-mediated diarrhea and colitis.
      ,
      • Abu-Sbeih H.
      • Ali F.S.
      • Wang X.
      • et al.
      Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis.
      ], including 613 patients (Suppl. Table 20). The risk of bias and methodological quality is displayed in Suppl. Table 21. In general, the quality of the included studies was good.
      Measured by clinical remission of symptoms, infliximab (5 mg/kg) was efficient in 87% of patients (95% CI 79% to 94%; 502 patients) and vedolizumab in a flat-dose regimen of 300 mg in 88% of patients (95% CI 62% to 100%; 111 patients) without any significant differences (P = 0.96; Fig. 5). Notably, biologics do not necessarily follow the same dosage regimens used for IBD [
      • Nielsen O.H.
      • Ainsworth M.A.
      Tumor necrosis factor inhibitors for inflammatory bowel disease.
      ,
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      ], because shorter intervals between dosages may be considered on a case-by-case basis for ICI-induced colitis [
      • Harris J.F.
      • Faleck D.
      Efficacy of infliximab dose escalation in patients with refractory immunotherapy-related colitis: a case series.
      ]. In patients failing an immunobiological agent, a shift out-of-class (i.e., TNF inhibitor versus anti-integrin) seems reasonable, and of notice no biomarkers predicting the therapeutic response have so far been identified.
      Figure thumbnail gr5
      Fig. 5Forest plot of efficacy of biologic therapy (infliximab and vedolizumab) in patients with immune-induced colitis.
      In the case of ICI-induced microscopic colitis [
      • Patil P.A.
      • Zhang X.
      Pathologic manifestations of gastrointestinal and hepatobiliary injury in immune checkpoint inhibitor therapy.
      ], budesonide appears to be efficient [
      • Hughes M.S.
      • Molina G.E.
      • Chen S.T.
      • et al.
      Budesonide treatment for microscopic colitis from immune checkpoint inhibitors.
      ], although data suggest that a more aggressive disease course may require potent immunomodulatory treatment regimens [
      • Choi K.
      • Abu-Sbeih H.
      • Samdani R.
      • et al.
      Can immune checkpoint inhibitors induce microscopic colitis or a brand new entity?.
      ].

      Discussion

      To our knowledge, this is the largest and most comprehensive analysis to evaluate the lower GI side effects of ICIs. We found that the incidence of anti-PD-1/PD-L1 antibody-induced diarrhea and colitis was 10% and 2%, respectively, whereas the incidence of diarrhea and colitis after ipilimumab treatment was 33%-50% and 7%–22%, respectively. The incidence of diarrhea and colitis of all grade were significantly higher for PD-1 inhibitors. However, the incidence of colitis grade 3–4 did not differ between the PD-1 and PD-L1 inhibitors. In addition, findings for the individual compounds were inconsistent, and the differences did not seem to be clinically relevant. Our findings might be explained by the different dose regimens included in the analysis. Thus, whether the incidence and severity of PD-1/PL-L1-induced diarrhea/colitis are dose dependent is unclear. In the present study the incidence of pembrolizumab-induced diarrhea grade 1–4 was dose dependent (data not shown). However, grade 3–4 diarrhea and colitis were not different between cohorts. In contrast, a meta-analysis of TRAEs related to different ICIs found atezolizumab 1,200 mg and pembrolizumab 2 mg/kg every 3 weeks being safer than other ICIs [
      • Chai Q.Q.
      • Du J.Y.
      • Zhu J.
      • et al.
      The differences in the safety and tolerability of immune checkpoint inhibitors as treatment for non-small cell lung cancer and melanoma: network meta-analysis and systematic review.
      ]. A high incidence of colitis was observed after ipilimumab in combination with nivolumab, with colitis occurring in 4%-8% of patients depending on regimen. For all combinations, the incidence of diarrhea and colitis was significantly higher than that of PD-1/PD-L1 inhibitors reflecting the general increased incidence of (severe) irAEs in patients receiving chemotherapy in combination with ICIs [
      • Chang C.Y.
      • Park H.
      • Malone D.C.
      • et al.
      Immune checkpoint inhibitors and immune-related adverse events in patients with advanced melanoma: a systematic review and network meta-analysis.
      ]. Platinum and taxane compounds were used in several different combinations. Besides, several platin-based studies did not report type of drug [
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      ,
      • Galsky M.D.
      • Mortazavi A.
      • Milowsky M.I.
      • et al.
      Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer.
      ,
      • Burtness B.
      • Harrington K.J.
      • Greil R.
      • et al.
      Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study.
      ,
      • Durm G.A.
      • Jabbour S.K.
      • Althouse S.K.
      • et al.
      A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14–179.
      ]. Thus, it was impossible to summarize findings to differentiate between the compounds. However, the prevalence of diarrhea after cisplatin or carboplatin has previously been reported to be low [
      • Bossi P.
      • Antonuzzo A.
      • Cherny N.I.
      • et al.
      Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines.
      ]. In addition, a retrospective recent study including 36,595 patients receiving platin-based chemotherapy found that only 0.2% developed endoscopic confirmed diarrhea and colitis independent of the drug used [
      • Abu-Sbeih H.
      • Mallepally N.
      • Goldstein R.
      • et al.
      Gastrointestinal toxic effects in patients with cancer receiving platinum-based therapy.
      ]. For patients receiving treatment with a taxane, all grade diarrhea has been reported in approximately 40% of patients independent of drug used [
      • Bossi P.
      • Antonuzzo A.
      • Cherny N.I.
      • et al.
      Diarrhoea in adult cancer patients: ESMO Clinical Practice Guidelines.
      ]. However, whereas no patients receiving nab-paclitaxel have been reported to have ≥ grade 3 toxicity, 0–27% of patients receiving docetaxel, and 3–7% of patients receiving paclitaxel had ≥ grade 3 diarrhea. Moreover, cases of severe colitis have been reported.
      When ICIs were combined with other agents, the incidence of diarrhea seemed to be additive, with up to 56% reported after combinations with TKIs. The influence of combination therapy on the frequency of colitis was minor and did not seem to be clinically relevant.
      Three main patterns of histopathologic presentation were identified: acute active colitis, chronic active colitis, and microscopic colitis-like. Despite the wide use of ICIs and relatively frequent GI AEs, no published prospective studies investigating the (optimal) biologic treatment of ICI-induced colitis and only a few ongoing studies (Suppl. Table 22) were identified. Current guidelines recommend infliximab or vedolizumab for persistent diarrhea/colitis grade 2 and grade 3–4 ([

      Haanen J, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl_4): iv119-iv142.

      ,
      • Thompson J.A.
      • Schneider B.J.
      • Brahmer J.
      • et al.
      NCCN guidelines insights: management of immunotherapy-related toxicities, Version 1.2020.
      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Schneider B.J.
      • Naidoo J.
      • Santomasso B.D.
      • et al.
      Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Guideline Update.
      ,
      • Dougan M.
      • Blidner A.G.
      • Choi J.
      • et al.
      Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.
      ] Suppl. Table 23). In our meta-analysis, infliximab and vedolizumab were equally effective, supporting this strategy. However, prospective studies are required to determine whether any subgroup may benefit from more specific treatment options. Thus, evidence suggests the launching of a paradigm shift toward more selective management of high-grade ICI-induced colitis using biologics as first-line therapies [
      • Abu-Sbeih H.
      • Ali F.S.
      • Wang X.
      • et al.
      Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis.
      ]. This strategy has the potential to prevent the development of a chronic inflammatory state and to avoid interruption of ICI treatment [
      • Abu-Sbeih H.
      • Ali F.S.
      • Wang X.
      • et al.
      Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis.
      ]. Moreover, the potential synergistic effect of TNF inhibitors and ICIs has been suggested [
      • Alvarez M.
      • Otano I.
      • Minute L.
      • et al.
      Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity.
      ,
      • Bertrand F.
      • Montfort A.
      • Marcheteau E.
      • et al.
      TNFalpha blockade overcomes resistance to anti-PD-1 in experimental melanoma.
      ,
      • Perez-Ruiz E.
      • Minute L.
      • Otano I.
      • et al.
      Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.
      ], and this strategy is currently being investigated in the TICIMEL trial (NCT03293784) (Suppl. Table 22).
      The biologic tocilizumab, an IL-6 receptor antagonist, a key drug in rheumatoid arthritis [
      • Yoshida Y.
      • Tanaka T.
      Interleukin 6 and rheumatoid arthritis.
      ], has shown clinical efficacy in 79% of the cohort in a retrospective study including 34 patients with a grade 3–4 irAE (pneumonitis, 35%; serum sickness, 35%; colitis, 3%) [
      • Stroud C.R.
      • Hegde A.
      • Cherry C.
      • et al.
      Tocilizumab for the management of immune mediated adverse events secondary to PD-1 blockade.
      ]. In addition, tocilizumab has been investigated in patients with ICI-induced colitis (COLAR trial; 19 patients with colitis/arthritis) in a preliminary study published after our final search of April 21, 2021 [

      Holsmtroem RB, Nielsen OH, Jacobsen S et al. COLAR: open-label clinical study of IL-6 blockade with tocilizumab for the treatment of immune checkpoint inhibitor-induced colitis and arthritis. J Immunother Cancer 2022; Epub ahead of print.

      ]. The authors concluded that tocilizumab showed promising clinical efficacy in the treatment of ICI-induced arthritis and/or colitis, as 80% of patients with colitis had ≥ 1 grade improvement in symptoms. Lastly, case reports with ustekinumab (2 cases), an IgG1k monoclonal antibody that binds with specificity to the p40 protein subunit of IL-12 and IL-23 [
      • Thomas A.S.
      • Ma W.
      • Wang Y.
      Ustekinumab for refractory colitis associated with immune checkpoint inhibitors.
      ], and the small molecule tofacitinib (4 cases), a pan-JAK inhibitor [
      • Bishu S.
      • Melia J.
      • Sharfman W.
      • et al.
      Efficacy and outcome of tofacitinib in immune checkpoint inhibitor colitis.
      ], have shown promise as alternatives to existing therapy, whereas the TNF inhibitor adalimumab has not been successful for ICI-induced colitis [
      • Lesage C.
      • Longvert C.
      • Prey S.
      • et al.
      Incidence and clinical impact of anti-TNFalpha treatment of severe immune checkpoint inhibitor-induced colitis in advanced melanoma: The Mecolit Survey.
      ]. Nonetheless, larger investigations with a sufficient number of observations are warranted.
      Treatment guidelines support the early use of glucocorticoids for ICI-induced diarrhea/colitis (Suppl. Table 23) [

      Haanen J, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl_4): iv119-iv142.

      ,
      • Thompson J.A.
      • Schneider B.J.
      • Brahmer J.
      • et al.
      NCCN guidelines insights: management of immunotherapy-related toxicities, Version 1.2020.
      ,
      • Brahmer J.R.
      • Abu-Sbeih H.
      • Ascierto P.A.
      • et al.
      Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.
      ,
      • Dougan M.
      • Blidner A.G.
      • Choi J.
      • et al.
      Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of severe gastrointestinal and hepatic toxicities from checkpoint inhibitors.
      ,
      • Brahmer J.R.
      • Lacchetti C.
      • Schneider B.J.
      • et al.
      Management of Immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline.
      ]. In general, data on the treatment of side effects are missing from clinical trials (Suppl. Table 3). Recent data have indicated that glucocorticoids may be associated with a potential risk of impaired antitumor efficacy [
      • Della Corte C.M.
      • Morgillo F.
      Early use of steroids affects immune cells and impairs immunotherapy efficacy.
      ,
      • Pan E.Y.
      • Merl M.Y.
      • Lin K.
      The impact of corticosteroid use during anti-PD1 treatment.
      ], but prospective data are still awaited. A meta-analysis, including 4,045 patients, showed that although glucocorticoids used to control cancer-related symptoms were associated with a negative effect on overall mortality, glucocorticoids used to mitigate adverse events did not negatively affect overall mortality [
      • Petrelli F.
      • Signorelli D.
      • Ghidini M.
      • et al.
      Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.
      ].
      Guidelines are based on expert experience and (small) observational studies, including patients who develop diarrhea/colitis following ICI monotherapy, primarily ipilimumab, or combinations of ICIs. Currently, several combinations of ICIs and chemotherapy or TKIs have been approved by the FDA and EMA, and combination therapy is the standard treatment for many cancers, such as non-small cell lung cancer, head and neck squamous cell carcinoma, gastric and esophageal cancer, and renal cell carcinoma. The incidence of all-grade diarrhea following such regimens was in our analysis additive and (very) high (17%-40% for chemotherapy and up to 56% for TKIs). In contrast, the incidence of grade 3–4 events was limited (around 2%) and the risk of severe colitis was low (approximately 0.5%), although colon perforation and fatal colitis-related events have been reported for all ICIs (Suppl. Table 17). The current guidelines (Suppl. Table 23) might result in the overuse of glucocorticoids and/or require a huge number of assessments, including colonoscopies; thus, the challenge is to distinguish between chemotherapy/TKI and ICI-induced diarrhea. Therefore, a more individualized and tailored approach for patients with low-grade diarrhea is suggested. In patients with diarrhea ≤ grade 2 and without abdominal symptoms as pain, bleeding etc., we suggest a more conservative approach with loperamide, hydration, and close monitoring, only initiating glucocorticoids in case of worsening or persistent symptoms.
      Detailed endoscopic and histologic information is critical to obtain an accurate assessment of ICI-related toxicity and to make more informed decisions on treatment. Thus, timely identification may result in treatment initiation at an early point [
      • Abu-Sbeih H.
      • Ali F.S.
      • Luo W.
      • et al.
      Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.
      ], thereby decreasing the rate of progression to severe flares and hospitalizations [
      • Abu-Sbeih H.
      • Ali F.S.
      • Wang X.
      • et al.
      Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor-induced colitis.
      ]. However, as stated above, this might require a large number of (invasive and costly) colonoscopies. Inflammatory biomarkers, including fecal lactoferrin and calprotectin, used as surrogate markers in patients with IBD, have demonstrated early promise. Given a similar pathophysiology process one may presume the role of these inflammatory biomarkers in patients with ICI-induced colitis. Currently, only few studies have been performed in patients with ICI-induced colitis. A study has shown that low fecal calprotectin levels at symptom onset was associated with a higher clinical response rate. Furthermore, patients with clinical responses had lower post-treatment calprotectin levels [
      • Abu-Sbeih H.
      • Ali F.S.
      • Alsaadi D.
      • et al.
      Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.
      ]. In another study, patients who achieved endoscopic remission after treatment had a significantly lower calprotectin concentration at symptom onset and after treatment compared with those without endoscopic remission [
      • Zou F.
      • Wang X.
      • Glitza Oliva I.C.
      • et al.
      Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis.
      ]. Thus, a simple stool test may be a novel tool for screening patients with diarrhea or colitis and stratifying patients who will need an endoscopy. Thus, inflammatory biomarkers have started to be incorporated into guidelines [
      • Abu-Sbeih H.
      • Ali F.S.
      • Alsaadi D.
      • et al.
      Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study.
      ,
      • Abej E.
      • El-Matary W.
      • Singh H.
      • et al.
      The utility of fecal calprotectin in the real-world clinical care of patients with inflammatory bowel disease.
      ,
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      ,
      • Manceau H.
      • Chicha-Cattoir V.
      • Puy H.
      • et al.
      Fecal calprotectin in inflammatory bowel diseases: update and perspectives.
      ]. Nevertheless, prospective validation is required [
      • Gong Z.
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      Immune checkpoint inhibitor-mediated diarrhea and colitis: a clinical review.
      ,
      • Kennedy L.C.
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      Immunotherapy-related colitis: an emerging challenge and a quest for prospective data.
      ].
      To distinguish between chemotherapy/TKI and ICI-induced diarrhea, as well as to identify patients with microscopic colitis (approximately 10% of patients) who can be treated with budesonide, a colonoscopy with biopsy should (still) be mandatory for all patients with persistent grade 2 diarrhea and patients with grade 3–4 diarrhea.
      Our study has several strengths. We employed a rigorous and comprehensive literature search focusing on both oncologic and hematologic patients. Only two studies were excluded because of missing data (i.e., only reporting TRAEs ≥ 10% or 15% and reporting no AEs; 304 patients) [
      • Spigel D.R.
      • Vicente D.
      • Ciuleanu T.E.
      • et al.
      Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331*.
      ,
      • Hamanishi J.
      • Mandai M.
      • Ikeda T.
      • et al.
      Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer.
      ]. Diverse patient cohorts from different parts of the world were included, broadening the generalizability of our findings. Our meta-analysis included several studies with relatively large datasets, which increased statistical power. Moreover, to our knowledge, this is the first and largest study of all grades of GI toxicity to include combination therapy. However, our study had some limitations. Study I included all identified phase I-IV studies reporting AEs in English, except for studies with escalation or<10 patients. Overall, 397 of the 411 studies used a specific version of the NCI-CTCAE. Thus, sensitivity analyses restricted to studies using the CTCAE were not performed. Because most studies only reported data on TRAEs and/or irAEs, we chose to use these data instead of data on AEs; thus, we may have underestimated the incidence of diarrhea/colitis. In addition, all studies in Study II investigating colitis therapy were retrospective, the number of patients was limited, and the criteria for inclusion of patients were heterogeneous. The identification of these studies depended on indexed terms regarding (entero-)colitis; thus, we may have missed some studies.
      Finally, it should be noted that the evaluation tool for diarrhea/colitis was based on CTCAE classification, solely relying on clinical symptoms and signs, which classifies diarrhea and colitis into grades 1–5 depending on severity [

      Haanen J, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28 (suppl_4): iv119-iv142.

      ,
      • Thompson J.A.
      • Schneider B.J.
      • Brahmer J.
      • et al.
      NCCN guidelines insights: management of immunotherapy-related toxicities, Version 1.2020.
      ]. In clinical practice, however, endoscopic evaluations with biopsies are performed on a case-by-case basis but are not specified in the CTCAE diagnosis and severity assessment. CTCAE (Suppl. Table 4) for diarrhea and colitis have been used interchangeably in most of the published literature, creating some confusion when discussing ICI-related GI toxicities. It is difficult to distinguish these conditions because they frequently overlap and may represent different levels of complications. Therefore, most recommendations for management are based on a combination of clinical symptoms and endoscopic signs, which in many cases are not the same.

      Conclusions

      No clinically meaningful differences in the incidence of immune-mediated colitis were found between PD-1 and PD-L1 inhibitors. However, colitis was more prevalent with anti-CTLA-4 therapy and ICI combinations. The incidence of all-grade diarrhea following ICI in combination with chemotherapy or TKIs was high, whereas only a few patients developed colitis. For these settings, we suggest a more tailored and individualized approach to managing patients with low-grade diarrhea. A more comprehensive grading system is warranted to incorporate the clinical signs and symptoms and the endoscopic and histologic components, similar to systems that are well established for IBD, such as the SCCAI [
      • Walmsley R.S.
      • Ayres R.C.
      • Pounder R.E.
      • et al.
      A simple clinical colitis activity index.
      ] or Mayo score [
      • Schroeder K.W.
      • Tremaine W.J.
      • Ilstrup D.M.
      Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.
      ]. Currently, no studies have yet investigated histopathologic findings after ICI in combination with chemotherapy or TKIs. Adequately powered prospective clinical trials, including quality of life and cost-effective analyses, are needed to confirm the abovementioned hypotheses and to validate potential biomarkers of inflammation and refine management.

      Additional information

      Author Affiliations: Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark (Dorte Lisbet Nielsen (DLN), Inna Markovna Chen (IMC)); Department of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, and Department of Physiotherapy and Occupational Therapy, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen Denmark (Carsten Bogh Juhl (CBJ)); Department of Gastroenterology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark (Ole Haagen Nielsen (OHN), Lauge Kellermann (LK)).

      Author Contributions

      DLN had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
      Study concept and design: DLN, CBJ, IMC, and OHN.
      Acquisition, analysis, or interpretation of data: DLN, CBJ, IMC, LK, and OHN.
      Drafting of the manuscript: DLN, CBJ, IMC, LK, and OHN.
      Critical revision of the manuscript for important intellectual content: DLN, CBJ, IMC, LK, and OHN.
      Statistical analysis: CBJ and DLN.
      Obtained funding: None.
      Administrative, technical, or material support: Professor Secretary Susanne Knygberg Christensen.
      Study supervision: OHN.

      Role of the Funder/Sponsor

      NA.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: [IMC reports research funding from Roche, Bristol Myers Squibb, Celgene, Genis, and advisory relationships with Amgen. None for DLN, CBJ, LK, and OHN].

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

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